PRevention Of BLeeding in hEmatological Malignancies With Antifibrinolytic (Epsilon Aminocaproic Acid)

Study Treatments: Epsilon aminocaproic acid (EACA) vs. standard prophylactic platelet transfusions.

Study Title: Randomized Trial of Epsilon Aminocaproic Acid versus Platelet Transfusions for the Prevention of Bleeding in Thrombocytopenic Patients with Hematological Malignancies. (PROBLEMA trial: PRevention Of BLeeding in hEmatological Malignancies with Antifibrinolytic agents (epsilon aminocaproic acid).

Phase: Randomized Phase 2

Eligible Population: Adult patients with acute or chronic thrombocytopenia in the setting of hematological malignancies.

Summary and Study Rationale: Compare EACA to standard prophylactic platelet transfusion for the prevention of bleeding in thrombocytopenic patients with hematological malignancies.

Study Design: prospective, randomized, controlled trial.

Study Endpoints: The primary endpoint is to compare the proportion of patients who develop major (grades 3-4) bleeding in each arm.

Diagnosis and Main Inclusion Criteria: Age > 18 with hematological malignancies. Acute or chronic thrombocytopenia with platelet counts < 20 x 10⁹/L.

Number of Patients: 100 patients, 50 patients in each arm

Duration of Patient Participation: 6 months

Approximate Duration of Study: 3 years

Dosage and Administration:1,000 mg twice a day orally

Prohibited Medications/Treatment: Hydroxyurea and procoagulant agents including DDAVP, recombinant Factor VII or prothrombin complex concentrate are prohibited in patients receiving EACA.

Safety Evaluations: Clinical assessment once weekly during the first 30 days and then monthly for 6 months, complete blood count and bleeding score twice weekly the first 30 days, and then according to standard of care or at discretion of treating physician.

Statistical Analysis

• Population Analysis
• Intention to treat (ITT) population: The ITT population includes all patients who are randomized to the study. Patients will be stratified and analyzed according to the treatment to which they were assigned.
• Safety Population: The safety population includes all patients who have received at least 1 dose of EACA. Patients included in the safety population will be analyzed according to the treatment they received.
• Per-protocol Population: The per-protocol population includes all patients who are randomized, receive at least one dose of study drug, and have no major protocol violations that could be expected to impact response data.
• Study Endpoints
• Primary Endpoint: is to compare at the end of the study, the proportion of patients with major bleeding during the study period among patients randomized to receive either EACA or standard of care prophylactic platelet transfusions.
• Secondary Endpoints include:
• Proportion of patients with any bleeding during the study period in each arm
• The total number of units of platelets transfused in each arm at the end of the study
• Quality of life as measured in each arm before the study and at the end of the study
• Safety in each arm
• Sample Size: This randomized, open-label phase II study is designed to compare the proportion of patient with major bleeding ever noted during the study. Patients will be assigned to receive prophylactic EACA (experimental arm) or prophylactic platelet (standard of care) in a 1:1 fashion. Previous studies suggest that the proportions of patients with major bleeding will be expected to be 8% and 30% in experimental arm and standard of care arm, respectively. With one sided Fisher's exact test, the sample size of 45 patients in each arm will achieve a power of 80% at the significance level of 5% to test whether prophylactic EACA can prevent major bleeding better than the standard of care. After adjusting for a 10% drop out rate, the actual required sample size will be 50 patients per arm. Therefore, the total sample size of the study will be 100 patients.
• Efficacy Analysis
• Primary Endpoint Analysis will be performed using a one-sided Fisher's exact test to compare the proportions of patients with major bleeding during the whole study between the two arms. The significance level is set at 0.05. This primary analysis will be based on the ITT population.
• Secondary Endpoint Analysis: one-sided t-test will be used to compare the total number of any bleeding episode noted during the study between the two arms. Two-sided t-test will be employed to compare the total number of units of platelets transfused at the end of the study between the two arms. Appropriate statistical tests (Chi-square test, t-test, Wilcoxon's rank sum test, etc.) will be conducted to compare the each score of the quality of life between the two arms before the study and at the end of the study, respectively. The change of each score of the quality of life from before the study to the end of the study will also be compared between the two arms. The safety in each arm will be also compared with Fisher's exact test. The analyses of secondary endpoints will be performed on the ITT population and the significance level will be kept at 0.05 for all tests.
• Safety Analysis: All patients receiving at least 1 dose of study drug will be considered evaluable for safety. Patients will be analyzed for safety according to the treatment which they received. Listings of laboratory test results will also be generated, and descriptive statistics summarizing the changes in laboratory tests over time will be presented. Exposure to study drug over time will also be summarized. The adverse events incidence rates, as well as the frequency of occurrence of overall toxicity, categorized by toxicity grades (severity) will be described for each treatment arm and be compared between two arms using two-sided Chi-square test or t-test.
• Quality of Life Analysis: Quality of life and health outcomes measures are being collected using EuroQoL instruments before the study and at the end of the study. Means and medians of raw scores of these questionnaires will be summarized for each treatment group for each domain and be compared between the two arms with t-test or Wilcoxon ranks sum test.
• Interim Analysis: Three interim analyses are planned after 11 patients in each arm have been randomized and their results have been obtained. Each interim analysis will focus on the primary endpoint, the proportion of patients with major bleeding ever noted during the study. To maintain an overall Type I error rate of 0.05 (1-sided), an O'Brien Fleming approach will be used which requires a 1-sided p-value < 0.001 at the first interim analysis (at 25% of total sample size). If this boundary is not crossed, then the study will continue and the second interim analysis will be conducted at 50% of the total sample side which requires a 1-sided significance level of 0.004. If this boundary is not crossed at the second interim analysis then, the study will continue and a third interim analysis will be conducted at 75% of the total sample side which requires a 1-sided significance level of 0.019. If this boundary is not crossed, the final primary analysis will be performed after completing 100% of the sample size using a 0.043 one-sided significance level.